Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and their germline precursors. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates both germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime candidate. In principle, similar germline-targeting strategies can be applied to other epitopes and pathogens.

A major goal of HIV-1 vaccine research is the design of immunogens capable of inducing broadly neutralizing antibodies (bnAbs) that bind to the viral envelope glycoprotein (Env). Poor binding of Env to unmutated precursors of bnAbs, including those of the VRC01-class, appears to be a major problem for bnAb induction. We engineered an immunogen that binds to VRC01-class bnAb precursors and immunized knock-in mice expressing germline-reverted VRC01 heavy chains. Induced antibodies showed characteristics of VRC01-class bnAbs, including a short light chain complementarity determining region 3 (CDRL3) and mutations that favored binding to near-native HIV-1 gp120 constructs. In contrast, native-like immunogens failed to activate VRC01-class precursors. The results suggest that rational epitope design can prime rare B cell precursors for affinity maturation to desired targets.

SummaryThe RV144 trial demonstrated 31% vaccine efficacy (VE) at preventing HIV-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (V1/V2) domain correlated inversely with infection risk2. We hypothesized that vaccine-induced immune responses against V1/V2 would selectively impact, or sieve, HIV-1 breakthrough viruses. 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V1/V2 at amino-acid positions 169 and 181. VE against viruses matching the vaccine at position 169 was 48% (CI: 18 to 66%; p=0.0036), whereas VE against viruses mismatching the vaccine at position 181 was 78% (CI: 35% to 93%; p=0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signatures sites (21±7 Å), and their match/mismatch dichotomy, suggest that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2 binding antibodies and reduced risk of HIV-1 acquisition and provide evidence that vaccine-induced V2 responses plausibly played a role in the partial protection conferred by the RV144 regimen.